The present invention discloses a new method for patient stratification in stable coronary disease (coronary disease: CAD) according to the patients' individual cardiac risks. Patients in the condition of a stable CAD are typically patients with angiographically proven CAD, i.e. with affected coronary arteries, with plaques on the inner walls of the coronary artery (atherosclerosis) and stenosis in a major coronary artery. CAD is considered a serious cardiac risk. CAD patients are considered as “stable” if the CAD does not manifest itself in the form of acute cardiovascular events.
In view of the imminent risk of future cardiovascular events it would be highly desirable to be able to distinguish within the group of patients with stable CAD between different groups according to their personal cardiac risk such that an “individual state of alert” can be determined for a particular patient in accordance with the risk group to which he has been allotted. Such grouping of patients is usually called “stratification”.
Distinguishing high risk patients from patients at moderate or low risk would allow a better selection of the most appropriate therapeutic strategy for a particular patient, avoiding, for example, underestimation of the cardiac risk and undermedication of high risk patients on the one hand and unnecessary therapeutic interventions, and the associated costs, with low risk patients on the other.
It is, therefore, an object of the present invention to provide a new method by which patients with stable CAD can be stratified in accordance with their personal cardiac risks, i.e. with respect to their individual risks concerning the future incidence of cardiovascular events.
As is further explained in detail below, the inventors have conducted a study to evaluate the potential usefulness of a number of analytes (biomolecules, biomarkers) which can be determined in the circulation of patients for a stratification of patients with stable CAD.
In the course of said study they have surprisingly found that a highly sensitive measurement of the concentration of the peptide procalcitonin (PCT) in the circulation of CAD patients in the range of very low physiological concentrations, which concentrations up to now were considered as being below diagnostic significance and, therefore, concentrations typical for normal healthy individuals, allows a useful stratification of CAD patients, and that the usefulness of such highly sensitive PCT determination can even be increased if the results obtained fro PCT are evaluated in combination with the results of the measurement of an analyte of another type action (a vasoactive analyte), exemplified by the so-called B-type (or brain) natriuretic peptide BNP.
Accordingly, the present inventions discloses a method as claimed in any of claims 1 to 6, and the use of a highly sensitive determination of PCT in the context of the prognosis of cardiovascular diseases for the risk stratification of patients, especially in arteriosclerosis and CAD, according to claims 7 and 8 respectively.
Procalcitonin (PCT), which is to be measured in accordance with the present invention, has become a well-established biomarker for sepsis diagnosis: PCT reflects the severity of bacterial infection and is in particular used to monitor progression of infection into sepsis, severe sepsis, or septic shock. It is possible to use PCT to measure the activity of the systemic inflammatory response, to control success of therapy, and to estimate prognosis (1) (2) (3) (4) (5). The increase of PCT levels in patients with sepsis correlates with mortality (6).
Whereas an increasing number of studies investigates the potential role of PCT in other infectious diseases like pneumonia, bacterial meningitis and malaria (7) (8) (9), no studies reported yet about the potential use of PCT in risk stratification of patients suffering from stable coronary artery disease (CAD). In vitro-studies showed, that PCT plays an important role during monocyte adhesion and migration and further has an effect on inducible nitric oxide synthase (iNOS) gene expression (10) (11) (12). The association between PCT levels and low-grade inflammation of the arterial wall in atherosclerosis and the potential effect on endothelial dysfunction has not been analyzed. Our prospective study examined the prognostic impact of PCT in a large group of consecutively enrolled stable angina patients on cardiovascular outcome to evaluate the potential clinical applicability of PCT measurements in CAD.
In the context of sepsis and related conditions, where the concentrations of PCT reach rather high physiological concentrations, PCT has been measured traditionally by means of an assay of the sandwich type using two monoclonal antibodies binding to different portions of the PCT molecule so that essentially only the complete PCT molecule is detected (see, for example, (1)). The typical functional assay sensitivity (FAS) of the typical two-sided chemiluminescence assay for PCT is 300 ng/L (0.3 ng/ml or 0.3 μg/L).
More recently new highly sensitive assays for the determination of PCT have been developed (28). The functional assay sensitivity (FAS, interassay CV<20%) of this new assay was <7 ng/1 PCT. Using this assay, typical PCT concentrations in healthy individuals could be determined. In 500 healthy individuals the range was <7 to 63 ng/L (<0.007 to 0.063 ng/ml), i.e. a range of concentrations well below 0.1 ng/ml. The determined median was 13.5 ng/L (95% confidence interval for the mean 12.6 to 14.7 ng/L).
In further improved form said sensitive PCT assay is available as PCT sensitive LIA (B.R.A.H.M.S AG, Hennigsdorf, Germany) having an analytical assay sensitivity of 0.01 ng/ml and a functional assay sensitivity (FAS) of at least 0.05 ng/ml. A related assay for the time-resolved amplified cryptate emission (TRACE) technology (Kryptor PCT, B.R.A.H.M.S AG, Hennigsdorf) has a functional assay sensitivity of 0.06 μg/L (0.06 ng/ml).
The more recent sensitive PCT assays have predominantly been used in connection with the guidance of antibiotic therapy in lower respiratory tract infections (community-acquired pneumonia, CAP; exacerbations of chronic obstructive pulmonary disease, COPD: see (29), (30), (31)). In the case of CAP antibiotic treatment is recommended on the basis of measured PCT concentrations as follows: strongly encouraged, greater than 0.5 μg/L; encouraged, greater than 0.25 μg/L; discouraged, less than 0.25 mg/L; strongly discouraged, less than 0.1 μg/L (29). In other words, concentrations of 0.1 μg/L (or 0.1 ng/ml) are considered as concentrations typical for healthy individuals.
The method of risk stratification of patients with stable coronary artery disease (stable CAD) is based on a differential evaluation of measured PCT concentrations which are below the value of 0.1 ng/ml for healthy individuals and which so far have not been used for diagnostic of prognostic purposes.
The invention is discussed in more detail in the following sections and the FIGS. 1 to 3 and Tables 1 to 7 mentioned therein. The Tables mentioned are found on separate pages at the end of the text of the description.